Fluoro steroids and methods of preparing the same



. a Unlted States PatentO ce Patented Apr. 2, 1968 3,376,293 FLUORU STEROIDS AND METHODS OF i PREPARING THE SAME O 5 Henry M. Kissman, Nanuet, N.Y.,.and Martin J. -Weiss, 5 g l' g H 1 01031? i I H l E Oradell, N.J., assignors to American Cyanamid Com- T 2 Alkaline E pany, New York, N.Y., a corporation of Maine Agent i i No Drawing. Continuation-impart of application Ser. No. E g 5 778,595, Dec. 8, 1958. This application Jan. 18, 1960, figgfgh E f Steriod E i anion I l i residue 21 Claims. (Cl. 260239.55)

ABSTRACT OF THE DISCLOSURE A process of preparing fluorine derivatives of the pregnane and androstane series and new steroids resulting I therefrom by reacting a salt the anion of which is derived from beta-dicarbonyl pregnane or beta-dicarbonyl androstane with perchloryl fluoride and subsequently with an alkaline agent in a hydrolytic solvent, is described. The products of the process are useful agents in one or more ofthe following glucocortoid, and androgenic and progestational fields.

The present application is a continuation-in-part of our copending application Ser. No. 778,595, filed Dec. 8, 1958, now abandoned.

This invention relates to a new method of preparing fluorine substituted steroids. More particularly, it relates to fluoro steroids of the pregnane and androstane series.

It is well known that fluorine substituted steroids such .as 9a-fluoro-16-a-hydroxypredisolone(triamcinolone) are highly active and useful antiarthritics. In US. Patent 2,857,403, 16a-fluorotestosterone is described as an ac- :tive' androgen. In the chemical literature, 2l-fluoroprogesterone is reported to have two to four times the progestational activity of progesterone. Also published reports indicate that the introduction of fluorine at the cx-position on the steroid nuclear has-profound effect on present which is alpha to a carbonyl group are capable, via the corresponding anion, of direct fluorination.

In this group, R is defined as hydrogen, hydroxy, carbalkoxy or a carboxy radical. The

group is usually attached to the steroid nucleus; however, it can be attached to the side chain as in the pregnane series. The following illustrates the reaction which takes place.

in which R is as defined above.

The process of the present invention is capable of inserting at least one fluorine atom in any position onthe steroid ring system Where a methylene or methyl group is alpha to a carbonyl group of the steroid nucleus. This would include the 2, 4, 16 and 21 positions. In the instance of the 21 position, the present process will insert one or two fluorine atoms depending upon the procedure used.

The starting materials used in the process of the present invention have been described in the prior art. The examples hereinafter include appropriate reference to the starting materials.

The present process is carried out by dissolving or suspending a carbon-acylated steroid of the keto-pregnane or the keto-androstane series as hereinbefore described in a solvent such as an aromatic hydrocarbon, a glycol, an alkoxy alcohol, dioxane pyridine, dirnethylformamide or, preferably, a lower aliphatic alcohol and adding thereto, if necessary, one equivalent of an alkaline agent sufiiciently strong to form a salt of the steroid. These alkaline agents can be, for example, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide sodium hydride and the like. The resulting solution or suspension is then maintained at a temperature of from about -60 C. to 50 C. and preferably within the range of about 20 to 0 C. while the perchloryl fluoride is bubbled through the reaction mixture until the reaction is substantially complete; This may require a period of from several minutes to one to two hours. Following completion of the reaction, the product is obtained by appropriate I treatment with a hydrolytic solvent such as water or an alcohol or mixture thereof and an alkaline agent such as a metal salt of a weak acid or an alkali metal alkoxide or by treatment with dilute mineral acid. This procedure effects deacylation and gives the desired fluoro steroid.

In the examples which follow the newly introduced fluorine atoms have been assigned. the alpha-configuration. This designation of configuration has been madein order to provide a more complete exposition of the present invention and in order that the specification shall constitute a more useful contribution to the art. However, the designated configuration is based on an analysis of infrared and ultraviolet absorption data presentlyappearing in the chemical literature and is therefore not to be interpreted except in relation to the state of the art presently known to organic chemists. It will be apparent that no part of the specification will be materially: defective if it should later be established that the configuration is the opposite of that deducible from data presently available to .workers in the field.

The following examples describe in detail the process of fluorination of steroids of the pregnane and androstane series.

To a cooled solution (l) of 0.535 g. (1.08 millimole) of 20-ethy-lenedioxy-2-methoxalyl-11e,17a,21-trihydroxyprogesterone (Australian application 23,672) in 25 cc. of absolute methanol is added 1.08 cc. of a 1 N methanolic sodium methoxide solution. Into the stirred solution is bubbled a vigorous stream of perchloryl fluoride for a few minutes. The mixture is then allowed to come to room temperature and is evaporated under reduced pressure. The residue is dissolved in a mixture of 20 cc. of chloroform and 6 cc. of water. The layers are separated and the water layer is washed further with chloroform. The combined chloroform layers are washed with a little water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is redissolved in cc. of methanol containing 0.19 g. of potassium acetate. The solution is allowed to reflux for one hour and is then evaporated under reduced pressure. The residue is mixed with 30 cc. of chloroform and 10 cc. of water and the layers are separated. The water layer is further extracted with a little chloroform and the combined chloroform layers are washed with a little water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is crystallized from ether to give 0.2 g. of product M.P. 224-226" C. Recrystallization from ethyl acetate afforded material with M.P. 224226 0;

To a solution of 0.622 g. (1.46 millimole) of -ethy1- enedioxy-2a-fluoro-1 1p,17a,21-trihydroxyprogesterone in 50 cc. of methanol is added 2 cc. of an 8% aqueous sulfuric acid solution. The mixture is allowed to reflux for one hour. Solvent is then distilled under reduced pressure while water is being added occasionally so as to keep the volume at approximately 40-50 cc. The cooled mixture is extracted thoroughly with chloroform and the combined extracts are washed with water, dried over magnesium sulfate, filtered and freed from chloroform under reduced pressure. The residue is crystallized from methylene chloride-ether to give 0.407 g. of crystalline solid with M.P. 2l6220 C.

Example 3.Preparation of 2l-fluoro-3B-hydroxy-5- pregnene-ZO-one To a cooled (20) solution of 1.8 g. (4.1 millimole) of 21-ethoxaly l-3;3-hydroxy-5-preguene20-one sodium salt [Chem Ber., 88, 878 (1955)] is added 4.1 cc. of a 1 N sodium methoxide solution. Into the stirred solution is passed a vigorous stream of perchloryl fluoride gas for a few minutes. The mixture is allowed to come to room temperature and is evaporated to a volume of about 30 cc. under reduced pressure. To the solution is added 2 g. of potassium acetate and the mixture is allowed to reflux for 1% hours and is then evaporated under reduced pressure. The residue is mixed withchloroform and water and the layers are separated. The water layer is extracted with some more chloroform and the combined chloroform extracts are washed with a little water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is crystallized from ether to give 0.92 g. of product, which can be recrystallized from methylene chloride-ether to give material melting at 184185 C.; [od +36.9 (c. 1.03 in chloroform).

Example 4.Preparation of 21-fluoroprogesterone To an azeotropically dried solution of 0.415 g. of 21.- fluoro-3/3-hydroxy-S-pregnene-ZO-one in 25 cc. of toluene and 3.8 cc. of cyclohexanone is added 2 cc. of aluminum isopropoxide (1 cc. of the toluene solution represented 0.252 g. of isopropoxide). The mixture is refluxed for 1% hours and is then steam distilled. The aqueous mixture is evaporated to dryness under reduced pressure and the residue is mixed with cu. of 5% aqueous hydrochloric acid solution and with cc. of ether. The layers are separated and the water phase is extracted thoroughly with ether. The combined ether extracts are washed with water and are then dried over magnesium sulfate, filtered and freed from solvent under reduced pressure. The residue is crystallized and recrystallized from ether; 0.23 g., M.P. 143445"; [(11 +206 (c. 1.005 in chloroform;

AQEB 240 mu (6 17,050)

Example 5. Preparation of 3-ethylenedioxy-1Get-fluoro- 5-androsten-17-one Sodium (0.075 g.) is dissolved in a mixture of 30 cc. of benzene and 2 cc. of methanol. Solvent is then distilled from the stirred mixture until the distillation temperature reaches C. To the resulting stirred suspension is then added 1 g. of dried B-ethyleuedioxy-S-androstene3,17-dione [J. Am. Chem. Soc. 76, 1359 (1954)] and 1 cc. of ethyl oxalate. The mixture is stirred at room temperature for 16 hours and is then extracted with several portions of 1% aqueous potassium hydroxide. The extracts are added to a 30% aqueous sodium dihydrogen-phosphate solution which is in turn extracted several times with chloroform. The combined chloroform extracts are Washed with a little water, dried over magnesium sul-. fate and freed from solvent under reduced pressure. The

residue is crystallized from ether to afford 0.795 g. of a white crystalline solid and can be recrystallized to give a material with melting point 161-163 C.; [111 103" (c. 0.793 CHCl To a solution of 1.67 g. of l6-ethoxalyl- 3-etlrylenedioxy-5-androsten-17-one, prepared as above, in

40 cc. of methanol which had been cooled to -10 is is then kept under reflux for 1.5 hours. The mixture is evaporated under reduced pressure and the residue is partitioned between water and chloroform. The water phase is extracted with chloroform and the combined chloroform extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from ether to give 0.323 g. of a white crystalline solid with melting point 226- 232 C.

Example 6.Preparation t of 3-ethylenedioxy-16a-fluoro- 17fl-hydroxy-5-androsteue To a suspension of 3-ethylenedioxy-16a-fluoro-5-androsteu-17-one (0.348 g.) in 10 cc. of methanol and 0.5 cc. of water is added 0.175 g. of. sodium borohydride and the stirred mixture is kept under reflux for 3 hours; It is then poured into 25 cc. of water and is extracted with several portions of chloroform. The combined chloroform extracts are washed with a little water, dried over magnesium sulfate and freed from solvent under reduced pressure. The residue is crystallized from methanol to give 0.307 g. with melting point 189-195 C.

Example 7.-Preparation of 16u-fluorotestosterone A solution of 0.3 g. of 3-ethylenedioxy-16a-fluoro-l7B- hydroxy-5-androstene-3-one in cc. of methanol containing 1 cc. of 8% aqueous sulfuric acid is allowed to reflux for one hour and then diluted with 30 cc. of methanol. The solution is stirred with a weakly basic anion exchange resin (OH form) until neutral. The resin is removed by filtration and is washed thoroughly with methanol. Filtrate and washings are combined and freed from solvents under reduced pressure. The residue is crystallized from ether to give 0.17 g. of a white crystalline substance with melting point 154-155 C. [(11 +117 (c. 0.501 in CHCl max.

Sodium (0.505 g.) is dissolved in a mixture of 80 cc. of benzene and 5 cc. of methanol. Solvent is then distilled from the solution until the distillation temperature reaches 80 C. To the cooled suspension is added 5 g. of ethyl oxalate and the mixture is stirred until the sodium methoxide is dissolved. There is then added 3.14 g. of dried progesterone and the mixture is stirred at room temperature for 24 hours. A heavy yellow precipitate forms during this time and 100 cc. of dry ether is added to complete precipitation. The solid is collected by filtration, washed with ether and dried under reduced pressure. There is thus obtained 5.87 g. of the disodium salt of 2,2-bisethoxalylprogesterone. This material is redissolved in 60 cc. of methanol, mixed with 20 cc. of 1 N methanolic sodium methoxide solution and the stirred mixture is cooled to 20 C. Perchloryl fluoride is passed into the stirred mixture at this temperature until the yellow color has disappeared. The mixture is evaporated partially under reduced pressure and there is then added 3 g. of potassium aceate. The reaction mixture is allowed to reflux for 1.5 hours and is then evaporated under reduced pressure. The residue is distributed between waterchloroform and the aqueous phase is extracted several times with chloroform. The combined chloroform extracts are washed with a little water, dried over magnesium sulfate and freed fro-m solvent under reduced pressure. The residual gum is crystallized from ether to yield 1.6g. of a crystalline product; M.P. 179180 C.; +218 (c. 0.837 in CHCl A 242 m (e 15,100),- AEE; 5.80 and 5.92 (carbonyl max.

region) The sodium salt of 21-ethoxalyl-3-hydroxy-5-pregnene- 20one [Chem Ber. 88, 878 (1955)] (0.9 g.) is suspended in cc. of methanol and 4.1 cc. of 1 N methanolic sodium methoxide is added. The stirred mixture is cooled to --10 C. and perchloryl fluoride gas is passed in for a few minutes. The mixture is then evaporated partially under reduced pressure to remove excess perchloryl fluoride. Another 4.1 cc. portion of the sodium methoxide solution is added and the mixture is again cooled to 10 C. and is then saturated with perchloryl fluoride. This treatment with methoxide and perchloryl fluoride is repeated once more and the reaction mixture is then partially evaporated, mixed with 1 g. of potassium acetate and kept at the boiling point for one hour. The suspension is evaporated under reduced pressure and the residue is distributed between water and chloroform. The water phase is extracted with several portions of chloroform and the combined chloroform extracts are washed with water, dried over magnesium sulfate and freed from solvent under reduced pressure. The residue is crystallized from ether to give 0.467 g. of a white crystalline solid which can be recrystallized from ether, M.P. ISO-154 C.

Example 10. Preparation of 21,21-difluoroprogesterone To a solution of 0.415 g. of 21,21-difluoro-3fl-hydroxy- S-pregnene-ZO-one in 25 cc. of toluene is added 3.8 cc. of cyclohexanone. Solvent is distilled from the mixture until 5 cc. has been collected. There is then added 0.5 g. of aluminum isopropoxide in 2 cc. of toluene and the mixture is allowed to reflux for 1% hours. Some 6 cc. of distillate are collected during this period. The reaction mixture is evaporated under reduced pressure and the residue is mixed with 25 cc. of 1 N hydrochloric acid. This mixture is extracted with several portions of ether and the combined ether extracts are Washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from pentane to give 0.273 g. of a white crystalline solid; M.P. 137- 140 C.;

REE; 5.77 p and 6.03, (carbonyl region) Example 11.Preparation of 2a-fluorotestosterone Sodium (0.092 g.) is dissolved in a mixture of 30 cc. of benzene and 2 cc. of methanol. Solvent is distilled from the stirred mixture until the distillation temperature reaches C. T o the suspension is then added 0.576 g. of dried testosterone and 1 g. of dried methyl oxalate. The mixture is stirred at room temperature for 16 hours and is then mixed with cold 1% potassium hydroxide (10 cc). The organic phase is separated and washed with another two 10 cc. portions of potassium hydroxide solution. The combined basic extracts are added to an ice cold mixture of 30 cc. of 0.1 N sulfuric acid and chloroform. The acid layer is separated and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate and freed from solvent under reduced pressure. There is obtained 0.4 g. of a yellow amorphous solid. To a cooled (10 C.) solution of 2-methoXalyl-17fi-hydroxy-4-androsten-3-one (1.8 g.), prepared as described above, in 50 cc. of methanol is added 5.8 cc. of 1 N methanolic sodium methoxide. The stirred solution is saturated with perchloryl fluoride gas and is then evaporated under reduced pressure. The residue is partitioned between chloroform and water and the aqueous phase is extracted several times with small portions of chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate and evaporated under re? duced pressure. The residue is redissolved in 40 cc. of methanol and to the solution is added 1 g. of potassium acetate. The mixture is allowed to reflux for 1% hours and is evaporated to. dryness under reduced pressure. The residue is partitioned between water and chloroform and the water phase is extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from methylene chloride-ether to afford 0.724 g. of a white solid with melting point 149-151 C.

Example 12.Preparation of iZOL-fiLIOIOtCSTOSteIOHE from 2-hydroxymethylenetestosterone (Z-hydroxymethylenel7/3-hydroxy-4-androsten-3-one) To solution of 1.05 g. of Z-hydroxymethylenetestosterone (F. Weisenborn et al. J. Amer. Chem. Soc, 76, 552, 1954) in 20 ml. of methanol, cooled to 1 0, is added 3 ml. of a 1 N methanolic sodium methoxide solution. The stirred, cooled mixture is treated with perchloryl fluoride gas for a few minutes and is then evaporated under reduced pressure. The residue is dissolved in a mixture of chloroform and water and the organic phase is dried over magnesium sulfate and is then evaporated under reduced pressure. The residue containing 2-fluoro-2- forrnyltestosterone is redissolved in 30 ml. of methanol and there is added 1 g. of anhydrous potassium acetate. The mixture is allowed to reflux for 1 hour and is then evaporated under reduced pressure. The residue is again distributed between water and chloroform and the chloroform phase is washed once with water and is dried over magnesium sulfate and freed from solvent under reduced pressure. The residue is crystallized from methylene chloride-ether to give Za-fluorOtestosterone.

Example 13.Preparation of 2-carboxytestosterone (2- carboxy-17;3-hydroxy-4-androsten-3'one) To a solution of 5.79 g. of testosterone in 15 ml. of dimethylformamide is added 40 ml. of a 2.8 M solution of magnesium methyl carbonate in dimethylformarnide [M. Stiles and H. L. Finkbeiner J. Amer. Chem. Soc. 81, 505 (1959)]. The stirred mixture is kept at 120 for two hours under a blanket of nitrogen and is then allowed to come to room temperature. The viscous mixture is added to a mixture of sulfuric acid and ice, and the resulting precipitate is filtered and washed free from sulfuric acid with ice water. The precipitate is dried over phosphorus pentox-ide under reduced pressure. For further purification, the solid is dissolved in cold 0.1 sodium hydroxide and the solution is quickly extracted with ether. The aqueous phase is acidified with ice sulfuric acid and the resulting precipitate of 2-carboxytestosterone is collected, washed with ice-water and dried as before;

W 242 mp (e 15,300) AER.

The viscous mixture containing the magnesium salt of 2-carboxytestosterone (prepared from 1.4 g. of testosterone as described in the preceeding example) in dimethylformamide is diluted with 10 cc. of dimethylformamide and is cooled to C. Perchloryl fluoride is bubbled through the stirred mixture until all the solid had gone into solution. Nitrogen gas is then blown through the solution in order to displace excess perchloryl fluoride and the solution is poured into 200 cc. of cold 6 N hydrochloric acid. The resulting precipitate of 2-carboxy-2- fiuorotestosterone is collected, washed thoroughly with water and is dried under reduced pressure. The precipitate is then suspended in 3 N hydrochloric acid and the stirred mixture is heated to 70 C. for 20 minutes to effect deearboxylation. The cooled suspension is extracted with chloroform and the extracts are washed successively with sodium bicarbonate solution and with water. The dried chloroform solution is evaporated under reduced pressure and the residue is crystallized and recrystallized from methylene chloride-ether to afford 2a-fiuorotestosterone (2u-fiuoro-17fi-hydroxy 4-androsten-3-one) with oon 240 my 15,112); REE; 5.90;:

max.

Example 15.'Preparation of 17B-acetoxy-2a-fiuorotestosterone (17,8-acetoxy-2u-fluoro-4-androsten-3-one) x3353 240 mu 15,100); region) AL; 5.79 and 5.90 (carbonyl Example 16.-'Preparation of 17fi-propionoxy-2ot-fiuorotestosterone (2ot-fluoro-17B-propionoxy 4-androsten-3- one) To an ice-cold solution of 612 mg. of 2u-fluorotestostertone (2a-fiuoro-17j8-hydroxy-androsten-3-one) in 7 cc. of pyridine is added 1 cc. of pr-opionic anhydride and the solution is stirred in an ice bath for several hours and is kept at room temperature overnight. The mixture is poured into 50 cc. of ice water and the solid which precipitates out on standing is collected, washed with water and is dried under reduced pressure. The material is recrystallized from acetone-hexane;

RES 241 111;].(6, 15,000); REE; 5.78;; and 5.90; (carbonyl region) Example 17.-Preparation of 17B-isobutoxy-2a-fiuorotestosterone (2u-fiuoro-17fi-isobutoxy-4-androsten-3-one) To an ice-cold solution of 612 mg. of 2a-fluorotestosterone (Zen-fluoro-17fi-hy-droxy-4-androsten-3-one) in 7 cc.

of pyridine is added 1.8 cc. of isobutyric anhydride and i the solution is stirred in an ice bath for 2 hours and at room temperature for 16 hours. The solution is poured into ice water, extracted with several portions of methylene chloride and the combined extracts are washed successively with saturated sodium bicarbonate solution and w 239;; (6, 15,130); Eff; 5.79;t and 5'90 (carbonyl region) Example 18.Preparation of 9oc-fll101'O-1IB-hYdIOXY-16a, 17u-isopropylidenedioxy 21 (tetrahydropyran 2-yloxy) -progesterone is recrystallized from ethyl acetate to aflford 0.4 g. with REE; 5.80;; and 5.96;]. (carbonyl region) Example 19.--Preparation of 2-ethoxalyl-9m-fluoro-11;3-

hydroxy 16a,17u-isopropylidenedioxy-21-(tetrahydropyran-Z-yloxy) -progesterone A solution of 0.389 g. of sodium in 8 cc. of methanol and 126 cc. of benzene is distilled until the distillation temperature reaches 80 C. To the cooled solution is' then added 3 cc. of ethyl oxalate and 2.7 g. of 9u-fluorollfi-hydroxy 16a,17a-isopropyli-denedioxy 21-(tetrahydropyran-Z-yloxy)-progesterone and the reaction mixture is stirred at room temperature for 16 hours. Some 250 cc. of ether is added and the dark red mixture is extracted 10' times with 25 cc. portions of ice cold 1% aqueous potassium hydroxide solution. The extracts are washed with ether and are then poured into enough 30% sodium dihydrogen phosphate solution to keep the mixture at pH 5-6. This mixture is in turn extracted quickly with several portions of chloroform and the combined extracts are washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The yellow residue (2.5 g.) is chromatographed on g. of silica gel from benzene. Elution with benzene containing increasing amounts of anhydrous ether brings down 0.8 g. of 2-ethoxalyl-9-a-fluoro-1lfi-hydroxy 16,17a-1S0p10pylidenedioxy ZI-(tetrahydropyran 2-yloxy)-progesterone as a yellow, amorphous solid which gives a strong positive ferric chloride test.

Example 20.Preparation of 2a,9a-difluoro-1lfi-hydroxy- 16a,17a-isopropylidenedioxy 21 (tetrahydropyran-Z- yloxy)-progesterone To a cold (-10 C.) solution of 0.62 g. of 2-ethoxalyloc-flllOl'O-lIfl-hYdI'OXY-1605,17oL-lSOPI'OPYlid6K16dlOXY 21- (tetrahydropyran-Z-yloxy)progesterone in 30 cc..of methanol is added 2 cc. of a l N methanolic sodium methoxide solution. Perchloryl fluoride gas is passed into solution until the latter is neutral. The mixture is then evaporated under reduced pressure and the residue is dissolved in a mixture of water and chloroform. The layers are separated and the water phase is extracted with several portions of chloroform. The combined chloroform extracts are washed with a little water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is redissolved in 30 cc. of methanol and to the solution is added 1 g. of potassium acetate. The mixture is allowed to reflux for one hour and is then evaportaed under reduced pressure. The residue is partioned between water and chloroform and the Water phase is extracted with several portions of chloroform. The combined chloroform extracts are washed with a little water, dried over magnesium sulfate and freed from solvent under reduced pressure. The residue (0.5 g.) is dissolved in benzene (5 cc.) and the colored solution is added to a column (13 x 1.5 cm.) of 15 g. of silica gel which had been Wetted down with benzene. Elution of the column with 100 cc. of benzene and 100 cc. of 15% benzene-ether affords fractions which are discarded. Further elution with 100 cc. of ether yields, after evaporation under reduced pressure, 0.25 g. of crystalline material which is recrystallized from ether to give 0.14 g. of product as a White crystalline solid; M.P. 210212 C.;

REE; 5.81 and 592 (carbonyl region) Example 21.Preparation of 2a,9a-difluoro-l l[-1,21- dihydroxy-16ot,17eisopropylidenedioxy-progesterone h 5.79,u and 5.92 1 (carbonyl region) Example 22.Preparation of 2a,9a-difiuoro-11,8-21-dihydroxy-16a,17ix-isopropylidenedioxyprogesterone 21- acetate To a cooled solution of 1.14 g. of 2a,9u-difiuoro-11/3, 2l-dihydroxy-l6a,l7et-isopropylidenedioxyprogesterone in 12.5 cc. of dry pyridine was added 2.5 cc. of acetic anhydride and the mixture is stirred in an ice bath for one hour and at room temperature for 16 hours. The mixture is then poured into 150 cc. of ice water and the resulting precipitate is collected, washed with water and dried in air. For further purification, the solid is dissolved in chloroform and the solution is washed with a little water and is dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from ether to afford a colorless powder with melting point 269-279, KBr

m 5.69,u, 5.76 and 5.89 4 (carbonyl region) A53 239 mu (6, 15,000)

Example 23.Preparation of 2a,9a-difiuoro-2l-hydroxy- 16a,17a-isopropylidenedioxyl-pregnene-3,11,20-trione vture for 16 hours. Pyridine is then removed under reduced pressure and the residue is thoroughly extracted with ethyl acetate. The ethyl acetate suspension is filtered through diatomaceous earth and the filtrate is Washed with dilute sulfuric acid and with water. The solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residual, crystalline 20,9ot-dlfill010- Z-hydroxy-l6a,17a-isopropylidenedioxy-4-pregnene 3,11- trione 21-acetate is dissolved in cc. of methanol and the solution is flushed with nitrogen. There is then added 2.5 cc. of a 1 N methanolic sodium methoxide solution and the mixture is stirred under nitrogen for 1 hour and is then neutralized with a few drops of acetic acid. The solvent is removed under reduced pressure and the residue is dissolved in a mixture of Water and chloroform. The chloroform phase is Washed with a little water and is dried over magnesium sulfate. The filtered solution is evaporated under reduced pressure and the residue is crystallized and recrystallized from ether to give the desired product with melting point 210'-215 C.,

mam 5.80 1 and 5.88 (carbonyl region), XQ QQ (6 15,600)

Example 24.Preparation of 2a-fiuoroprogesterone To 10.0 g. of 3B-hydroxy-pregnen-ZO-one is added 250 cc. of ethylene glycol and 25 cc. of ethylene glycol is distilled off at 15-20 mm. To the reaction mixture is added 0.450 g. p'toluenesulfonic acid and 25 cc. ethylene glycol, and material is slowly distilled at 15 mm. for 1 hour. The mixture is cooled in an ice bath, and the solid is collected by filtration, Washed well with water and dried to yield 10.88 g. The product, 20-ethylenedioxy-3;3 hydroxy-5-pregnen-20one, is recrystallized from ethanol.

Some 40 cc. of distillate is collected from a mixture of 3.25 g. 20-ethylenedi0xy-3 8-hydroxy5-pregnen-20-one prepared above, cc. of toluene, and 27.66 cc. cyclohexanone. To the reaction mixture is added 14.55 cc. aluminum isopropoxide solution (concentration 0.25 g./ cc. in toluene) and the mixture is stirred at reflux for 80 minutes with intermittent collection of distillate. The solvent is removed under reduced pressure, and the residue is triturated with ether to afford 1.63 g. The product is recrystallized from ether; M.P. 187-189.

A solution of 0.114 g. of sodium in 3.7 cc. methanol and 45 cc. benzene is distilled until the distillation temperature reaches 80 C. To the cooled solution is then added 1.5 cc. ethyl oxalate and 1.63 g. ZO-ethylenedioxyprogesterone prepared above in 20 cc. benzene, and the reaction mixture is stirred at room temperature for 21 hours. Some 200 cc. of ether is added to the red solution, and the mixture is extracted with several 30 cc. portions of ice cold 1% aqueous potassium hydroxide solution. The extracts are Washed with ether and are then poured into enough 30% sodium dihydrogen phosphate solution to keep the mixture at pH 5-6. This mixture is in turn extracted quickly with several portions of chloroform, and the combined extracts are Washed with water, dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated under reduced pressure to leave 1.92 g. of Z-ethoxalyl-ZO-ethylenedioxyprogesterone as a yellow amorphous solid which gives a strong positive ferric chloride test.

To a cooled (20) solution of 1.92 g. 2-ethoxalyl-20- ethylenedioxyprogesterone prepared above in 50 cc. methanol is added 8.4 cc. 1 N methanolic sodium methoxide solution. The stirred, cooled mixture is saturated With perchloryl fluoride gas for three minutes and is then evaporated under reduced pressure. The residue is dissolved in a mixture of 30 cc. chloroform and 30 cc. water. The water phase is washed With two 10 cc. portions of chloroform, and the combined chloroform solutions are washed with a little Water, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue is triturated with methanol to give white crystals of ZO-ethylenediOXy-Za-fluoroprogesterone; M.I. 168176;

A mixture of 1.3 g. of 20-ethylenedioxy-2a-fluoro- 5.91 (carbonyl region) REE; 5.91 1 (carbonyl region) Example 25.-Preparation of Zen-fillOIO-Zl -hydroxy-4- pregnene-3,20-dione (2a fluorodeoxycorticosterone) To a suspension of sodium ethoxide (prepared from 0.1 g. of sodium) in 30 cc. of anhydrous benzene is added 0.833 g. (2 moles) of deoxycorticosterone acetate ZO-ethylene ketal [F. Sondheimer and Y. Klibansky) Tetrahedron 5, (1959)] and 2 cc. of diethyl oxaae. The mixture is stirred at room temperature for 16 hours and is then diluted with ether. The mixture is extracted with water and three times with 20 cc. ortions of cold 1% aqueous potassium hydroxide solution. Each portion of extract is washed with a little ether and is added to a mixture of sodium dihydrogen phosphate solution and chloroform. The layers are separated and the aqueous phase is extracted with additional portions of chloroform until these extracts no longer give a positive enol test (ferric chloride). The combined chloroform extracts are washed with water, dried and freed from solvents under reduced pressure to leave 0.89 g. of an orange gum. This is dissolved in 20 cc. of methanol, and to the cooled solution (20 C.) is added 5 cc. of l N sodium methoxide solution. The mixture is saturated quickly with a vigorous stream of perchloryl fluoride and is then evaporated. The residue is dissolved in methylene chloride and the solution is washed with 2% aqueous sodium hydroxide and with water. The organic phase is dried over magnesium sulfate, evaporated and the residue is dissolved in methanol (20 cc.) containing 0.5 g. of potassium acetate. The mixture is kept under reflux for 70 minutes and is then evaporated. The residue is partitioned between water and methylene chloride and the organic phase is dried and evaporated. The residual 2c:- fluorodeoxycorticosterone ZO-ethylene ketal crystallizes when triturated with ether. It is collected and dissolved in 20 cc. of methanol containing 1 cc. of 8% aqueous sulfuric acid. The mixture is refluxed for 1 hour and is then neutralized by stirring with a weakly basic anion exchange resin and the suspension is freed from the resin by filtration. Evaporation of the filtrate gives a residue which is crystallized and recrystallized from ether; M.P. 138-141 C.;

X333 242 a (6 15,330 x3333; 5.85;.L)

5.90 1 (with shoulder at Example 26.Preparation of 2a-fluoro-21-hydroxy-4- pregnene-3,20-dione ZI-acetate (Za-fluorodeoxycorticosterone acetate) max.

5.70 and 5.90 11 (carbonyl region);

urn 2 3 m We claim: 1. A process of preparing fluorine derivatives of the pregnane and androstane series which comprises reacting a salt the anion of which is derived from the group consisting of a beta-dicarbonyl .pregnane and a beta-dican. bonyl androstane with perchloryl fluoride and subse quently with an alkaline agent in the presence of a hydrolytic solvent.

2. A process of preparing fluorine derivatives of the pregnane series which comprises reacting a salt the anion of which is derived from an alpha-alkoxalyl keto-pregnane with perchloryl fluoride and subsequently with an alkaline agent in the presence of a hydrolytic solvent.

3. A process of preparing fluorine derivatives of the androstane series which comprises reacting a salt the anion of which is derived from an alpha-alkoxalyl ketoandrostane with perchlorylfluoride and subsequently with an alkaline agent in the presence of a hydrolytic solvent.

4. A process of preparing ZO-ethylenedioxy-2e-fluoro- 1lfl,17u,2l-trihydroxyprogesterone which comprises react:

ing an alkali metal salt of ZO-ethylenedioxy-2-methoxalyl-.

11,8,17a,21-trihydroxyprogesterone with perchloryl fluoride followed by reaction with an alkaline agent in a hydrolytic solvent.

5. A process of preparing 2a-fluoro-11fi,17u,21-trihydroxy-progesterone which comprises reacting an alkali metal salt of ZO-ethylenedioxy-Z-methoxalyl-11fl,17u,2ltrihydroxy-progesterone with perchloryl fluoride subsequently hydrolyzing the reaction product with an alkaline agent followed by acid hydrolysis and recovering said compound.

6. A process of preparing 21-fluoro-3B-hydroxy S-pregnene-20-one which comprises reacting 21-ethoxa1yl-3B- hydroxy-S-pregnene-20-one sodium salt with perchloryl fluoride subsequently hydrolyzing the reaction product with an alkaline agent and recovering said compound.

7. A process of preparing 3-ethylenedioxy-16a-fluoro-5- androstene-3,17-dione which comprises reacting an alkali metal salt of 16 ethoxalyl 3ethylenedioxy-S-androstene- 3,17-dione with perchloryl fluoride and subsequently with an alkaline agent in a hydrolytic solvent.

8. A process of preparing 3-ethylenedioxy-l6a-fluoro- 17fl-hydroxy-5-androstene-3 -one which comprises reacting an alkali metal salt of 16 ethoxalyl 3-ethylenedioxy-5- androstene-3,17-dione with perchloryl fluoride treating the reaction product with an alkaline agent in a hydrolytic solvent and reducing the reaction product thereof with sodium borohydride.

9. A process of preparing 16a-fluorotestosterone which comprises reacting an alkali metal salt of 16 ethoxalyl 3-ethylenedioxy S-androstene 3,17-dione with perchloryl fluoride treating the reaction product with an alkaline agent in a hydrolytic solvent and reducing the reaction product thereof with sodium borohydride followed by acid hydrolysis and recovering said product.

10. A process of preparing 2a-fluorotestosterone which comprises reacting an alkali metal salt of Z-methoxalyl testosterone with perchloryl fluoride and finally with an alkaline agent in a hydrolytic solvent.

11. A process of preparing 2a,2l-difluoroprogesterone which comprises reacting the dialkali metal salt of 2,21- ethoxalylprogesterone with perchloryl fluoride and subsequently with an alkaline agent in a hydrolytic solvent.

12. A process of preparing 21,21-difluoro 20-keto- 'pregnenes which comprises reacting an alkali metal salt of 21-ethoxalyl-20-keto-pregnene with perchloryl fluoride treating the reaction mixture with excess alkali metal alkoxide and subsequently with perchloryl fluoride and finally with an alkaline agent in a hydrolytic solvent.

13. A compound selected from the group consisting of 2a-fluoroprogesterone and 2a,2l-difluoroprogesterone.

14. The compound 204,2l-difluoroprogesterone.

15. The compound 2a-fluoroprogesterone.

16. The compound 2u-fluorotestosterone.

13 14 17. The compound 2a,9u-difluor0 11 5,21-dihydr0xy- References Cited 16a,17a-isopropylidenedioxyprogesterone UNITED STATES P N I compound 206,906-difillOIO-21-h} dI'OXy'16Ct,1706- et all 1sopropyhdened10Xy-4-pregnene-3,11,20-tr1one. 5 3 011 11 95 Hogg et aL 2 39 55 19. The compound 16-ethoxa1yl 3-ethy1enedioxy-5- OTHER REFERENCES androsten-17-one.

20. 21,21-Difluoro-A -pregnene-3,ZO-dione. 511 5 22 3 2 g 1956 21. A method for the production of a 21,21-difluoro- Nakanish et A'b 5259, C'JCL 1959. ZO-keto steroid of the pregnane series which comprises 10 reacting a 21-a1koXya1y1-20-ket0 pregnane with perchloryl LEWIS GOTTS, Primary Examiner. fluoride and treating the compound formed thereby with L H GASTON, LIEBMAN, Examiners.

Zigzag: form the corresponding 21,2l-d1fiu0ro-2O-keto- H A FRENCH, Assistant Examiner. 

